tbuckley/cabot-search huggingface dataset:
Development of the novel ACLY inhibitor 326E as a promising treatment for hypercholesterolemia
Authors: Zhifu Xie, Mei Zhang, Qian Song, Long Cheng, Xinwen Zhang, Gaolei Song, Xinyu Sun, Min Gu, Chendong Zhou, Yangming Zhang, Kexin Zhu, Jianpeng Yin, Xiaoyan Chen, Jingya Li, Fajun Nan
Journal: Acta Pharmaceutica Sinica B (2022)

Hepatic cholesterol accumulation is an important contributor to hypercholesterolemia, which results in atherosclerosis and cardiovascular disease (CVD). ATP-citrate lyase (ACLY) is a key lipogenic enzyme that converts cytosolic citrate derived from tricarboxylic acid cycle (TCA cycle) to acetyl-CoA in the cytoplasm. Therefore, ACLY represents a link between mitochondria oxidative phosphorylation and cytosolic de novo lipogenesis. In this study, we developed the small molecule 326E with an enedioic acid structural moiety as a novel ACLY inhibitor, and its CoA-conjugated form 326E-CoA inhibited ACLY activity with an IC50 = 5.31 ± 1.2 μmol/L in vitro. 326E treatment reduced de novo lipogenesis, and increased cholesterol efflux in vitro and in vivo. 326E was rapidly absorbed after oral administration, exhibited a higher blood exposure than that of the approved ACLY inhibitor bempedoic acid (BA) used for hypercholesterolemia. Chronic 326E treatment in hamsters and rhesus monkeys resulted in remarkable improvement of hyperlipidemia. Once daily oral administration of 326E for 24 weeks prevented the occurrence of atherosclerosis in ApoE-/- mice to a greater extent than that of BA treatment. Taken together, our data suggest that inhibition of ACLY by 326E represents a promising strategy for the treatment of hypercholesterolemia.
Neoadjuvant Trastuzumab and Pyrotinib for Locally Advanced HER2-Positive Breast Cancer (NeoATP): Primary Analysis of a Phase II Study
Authors: Wenjin Yin, Yaohui Wang, Ziping Wu, Yumei Ye, Liheng Zhou, Shuguang Xu, Yanping Lin, Yueyao Du, Tingting Yan, Fan Yang, Jie Zhang, Qiang Liu, Jinsong Lu
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Despite accumulating evidence on dual blockade of HER2 for locally advanced HER2-positive breast cancer, no robust evidence supports the addition of pyrotinib to trastuzumab in the neoadjuvant setting. The NeoATP trial aimed to evaluate the efficacy and safety of pyrotinib with neoadjuvant trastuzumab and chemotherapy. Patients and Methods: The phase II NeoATP trial included female patients with histologically confirmed stage IIA to IIIC and HER2-positive primary invasive breast cancer. Eligible patients received pyrotinib and trastuzumab with weekly paclitaxel–cisplatin neoadjuvant chemotherapy for four cycles. The primary endpoint was pathologic complete response (pCR; ypT0 ypN0) rate. Key secondary endpoints included locoregional pCR (ypT0/is ypN0) rate, biomarker analysis, and safety. Results: Among 53 enrolled patients (median age, 47 years; 73.58% stage III), 52 completed the study treatment and surgery. Overall, 37 patients (69.81%) achieved pCR. For women with hormone receptor–negative and –positive tumors, the pCR rates were 85.71% and 59.38% (P = 0.041), while the corresponding rates were 69.23% and 70.00%, respectively, for those with and without PIK3CA mutation (P = 0.958). The most frequently reported Grade 3 to 4 adverse events were diarrhea (45.28%), leukopenia (39.62%), and neutropenia (32.08%). No deaths occurred, and no left ventricular ejection fraction &amp;lt;50% or &amp;gt;10 points drop from baseline to before surgery was reported. Conclusions: The addition of pyrotinib to trastuzumab plus chemotherapy is an efficacious and safe regimen for patients with HER2-positive locally advanced breast cancer in the neoadjuvant setting. The randomized controlled clinical trial is warranted to validate our results.
Clinical significance and molecular annotation of cellular morphometric subtypes in lower-grade gliomas discovered by machine learning
Authors: Xiao-Ping Liu, Xiaoqing Jin, Saman Seyed Ahmadian, Xu Yang, Su-Fang Tian, Yu-Xiang Cai, Kuldeep Chawla, Antoine M Snijders, Yankai Xia, Paul J van Diest, William A Weiss, Jian-Hua Mao, Zhi-Qiang Li, Hannes Vogel, Hang Chang
Journal: Neuro-Oncology (2022)

Abstract Background Lower-grade gliomas (LGG) are heterogeneous diseases by clinical, histological, and molecular criteria. We aimed to personalize the diagnosis and therapy of LGG patients by developing and validating robust cellular morphometric subtypes (CMS) and to uncover the molecular signatures underlying these subtypes. Methods Cellular morphometric biomarkers (CMBs) were identified with artificial intelligence technique from TCGA-LGG cohort. Consensus clustering was used to define CMS. Survival analysis was performed to assess the clinical impact of CMBs and CMS. A nomogram was constructed to predict 3- and 5-year overall survival (OS) of LGG patients. Tumor mutational burden (TMB) and immune cell infiltration between subtypes were analyzed using the Mann-Whitney U test. The double-blinded validation for important immunotherapy-related biomarkers was executed using immunohistochemistry (IHC). Results We developed a machine learning (ML) pipeline to extract CMBs from whole-slide images of tissue histology; identifying and externally validating robust CMS of LGGs in multicenter cohorts. The subtypes had independent predicted OS across all three independent cohorts. In the TCGA-LGG cohort, patients within the poor-prognosis subtype responded poorly to primary and follow-up therapies. LGGs within the poor-prognosis subtype were characterized by high mutational burden, high frequencies of copy number alterations, and high levels of tumor-infiltrating lymphocytes and immune checkpoint genes. Higher levels of PD-1/PD-L1/CTLA-4 were confirmed by IHC staining. In addition, the subtypes learned from LGG demonstrate translational impact on glioblastoma (GBM). Conclusions We developed and validated a framework (CMS-ML) for CMS discovery in LGG associated with specific molecular alterations, immune microenvironment, prognosis, and treatment response.
Direct-Acting Antivirals as Primary Treatment for Hepatitis C Virus–Associated Indolent Non-Hodgkin Lymphomas: The BArT Study of the Fondazione Italiana Linfomi
Authors: Michele Merli, Sara Rattotti, Michele Spina, Francesca Re, Marina Motta, Francesco Piazza, Lorella Orsucci, Andrés J.M. Ferreri, Omar Perbellini, Anna Dodero, Daniele Vallisa, Alessandro Pulsoni, Armando Santoro, Paolo Sacchi, Valentina Zuccaro, Emanuela Chimienti, Filomena Russo, Carlo Visco, Anna Linda Zignego, Luigi Marcheselli, Francesco Passamonti, Stefano Luminari, Marco Paulli, Raffaele Bruno, Luca Arcaini
Journal: Journal of Clinical Oncology (2022)

We prospectively treated patients with hepatitis C virus (HCV)-associated indolent lymphomas with genotype-appropriate direct-acting antivirals (DAAs) with the aim to evaluate virologic and hematologic outcomes. No prospective studies in this setting have been published so far.FIL_BArT is a prospective, multicenter, phase II trial that evaluated genotype-appropriate DAAs in untreated HCV-positive patients with indolent lymphomas without criteria for immediate conventional antilymphoma treatment. The primary objective was sustained virologic response, whereas the main secondary objectives were overall response rate of lymphoma and progression-free survival.Forty patients were enrolled, including 27 with marginal zone lymphoma. Median age was 68 years. Extranodal sites were involved in 14 cases (35%). Main genotypes were 1 in 16 patients and 2 in 21 patients. All patients received genotype-guided DAAs: 17 ledipasvir/sofosbuvir, eight sofosbuvir plus ribavirin, and 15 sofosbuvir/velpatasvir. All patients achieved sustained virologic response (100%). DAAs were well tolerated, with only two grade 3-4 adverse events. Overall response rate of lymphoma was 45%, including eight patients (20%) achieving complete response and 10 (25%) partial response, whereas 16 exhibited stable disease and six progressed. With a median follow-up of 37 months, two patients died (3-year overall survival 93%; 95% CI, 74 to 98) and three additional patients progressed, with a 3-year progression-free survival of 76% (95% CI, 57 to 87).HCV eradication by DAAs was achieved in 100% of HCV-positive patients with indolent lymphomas not requiring immediate conventional treatment and resulted in non-negligible rate of lymphoma responses. Treatment with DAAs should be considered as the first-line therapy in this setting.
21MO Limited benefit of molecular profiling in patients with low-grade endometrial cancer
Authors: S. Vrede, J. Kasius, J. Bulten, W.J. Van Weelden, D. Boll, M.C. Vos, A. Van Altena, X. Matias-Guiu, J. Asberger, E. Colas, A. Gil-Moreno, J. Huvila, V. Weinberger, F. Amant, M. Snijders, H. Küsters-Vandevelde, A. Eijkelenboom, R. Kruitwagen, C. Reijnen, J.M. Pijnenborg
Journal: Annals of Oncology (2022)
45TiP A randomized, molecular driven phase II trial of carboplatin-paclitaxel-bev vs carboplatin-paclitaxel-bev-rucaparib vs carboplatin-paclitaxel-rucaparib, selected according to HRD status, in patients with advanced ovarian cancer
Authors: G. Scambia, V. Salutari, L. Musacchio, S. Siena, S. Pignata, L. Zavallone, G. Valabrega, G. Cormio, A.M. Mosconi, C. Ricci, V. Ghizzoni, M.V. Carbone, E. Giudice, F. Camarda, C. Nero, F. Tronconi, D. Lorusso
Journal: Annals of Oncology (2022)
42P Real-life data on treatment with poly (ADP-ribose) polymerase inhibitor (iPARP), in patients over 65 years of age with ovarian cancer: A current need
Authors: M. Martinez Cutillas, Y. Garitaonaindia Diaz, B. Nunez Garcia, M. Blanco Clemente, C. Traseira Puchol, R. Aguado, G. Visedo, A. Gónzalez Sánchez, D.I. Ruiz de Domingo, M.M. Sánchez Del Corral, M.A. Gonzalez Del Alba Baamonde, J.C. Sanchez Gonzalez, B. Cantos Sanchez de Ibarguen, M. Mendez Garcia, M. Provencio Pulla, C. Maximiano Alonso
Journal: Annals of Oncology (2022)
Circulating Tumor DNA Kinetics Predict Progression-Free and Overall Survival in EGFR TKI–Treated Patients with <i>EGFR</i>-Mutant NSCLC (SWOG S1403)
Authors: Philip C. Mack, Jieling Miao, Mary W. Redman, James Moon, Sarah B. Goldberg, Roy S. Herbst, Mary Ann Melnick, Zenta Walther, Fred R. Hirsch, Katerina Politi, Karen Kelly, David R. Gandara
Journal: Clinical Cancer Research (2022)

Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome.
31P Survival outcomes in BRCA pathogenetic mutated, variant of unknown significance, and wild type ovarian cancer patients treated with PARP inhibitors
Authors: L. Musacchio, C. Marchetti, S.M. Boccia, C. Cassani, J. Ventriglia, V. Salutari, F. Camarda, V. Ghizzoni, E. Giudice, M.V. Carbone, S. Pignata, G. Scambia, D. Lorusso
Journal: Annals of Oncology (2022)
Activation of CD81 <sup>+</sup> skin ILC2s by cold-sensing TRPM8 <sup>+</sup> neuron-derived signals maintains cutaneous thermal homeostasis
Authors: Ming Xu, Chao Li, Jie Yang, Amy Ye, Liping Yan, Beng San Yeoh, Lai Shi, Yu Shin Kim, Joonsoo Kang, Matam Vijay-Kumar, Na Xiong
Journal: Science Immunology (2022)

As the outermost barrier tissue of the body, the skin harbors a large number of innate lymphoid cells (ILCs) that help maintain local homeostasis in the face of changing environments. How skin-resident ILCs are regulated and function in local homeostatic maintenance is poorly understood. We here report the discovery of a cold-sensing neuron-initiated pathway that activates skin group 2 ILCs (ILC2s) to help maintain thermal homeostasis. In stearoyl-CoA desaturase 1 (SCD1) knockout mice whose skin is defective in heat maintenance, chronic cold stress induced excessive activation of CCR10 − CD81 + ST2 + skin ILC2s and associated inflammation. Mechanistically, stimulation of the cold-sensing receptor TRPM8 expressed in sensory neurons of the skin led to increased production of IL-18, which, in turn, activated skin ILC2s to promote thermogenesis. Our findings reveal a neuroimmune link that regulates activation of skin ILC2s to support thermal homeostasis and promotes skin inflammation after hyperactivation.
27MO Integrated digital pathology and single-cell analysis identify the spatial and temporal evolution of immune cells networks in epithelial ovarian cancer
Authors: E. Ghisoni, F. Benedetti, P. Cunnea, N. Fahr, D.C. Gulhan, A. Minasyan, M. Desbuisson, A. Grimm, D. Barras, J. Dagher, E. Fortis, S. Rusakiewicz, S. Tissot, S.A. Mastroyannis, E. Swisher, L. Kandalaft, J. Tanyi, C. Fotopoulou, G. Coukos, D. Dangaj
Journal: Annals of Oncology (2022)
38P Impact of 1-year COVID-19 pandemic in patients with ovarian carcinoma treated with chemotherapy based on a global data network
Authors: L.M. Manso Sanchez, A. Madariaga Urrutia, G. Hernández-Ibarburu, R. Sanchez Bayona, P. Tolosa Ortega, L. Lema Roso, M. Alva, A. Modrego, P. Serrano, L. Paz-Ares
Journal: Annals of Oncology (2022)
Risk factors and clinical impact associated with infections caused by different types of carbapenem-resistant Klebsiella pneumoniae in China: A clinical study from 2014 to 2017
Authors: Qiaoling Sun, Xuemei Yang, Yonglu Huang, Yi Li, Jianping Lin, Daihai He, Congcong Liu, Sheng Chen, Rong Zhang
Journal: Journal of Infection (2022)
68Ga-FAPI-46 and 18F-FDG in Advanced Metastatic Pancreatic Cancer
Authors: Fatemeh Kaghazchi, Ghasemali Divband, Hamidreza Amini, Zohreh Adinehpour, Ramin Akbarian Aghdam
Journal: Clinical Nuclear Medicine (2022)

Recently imaging with new PET radiotracers that act as fibroblast activation protein inhibitors (FAPIs) showed promising results in oncology and even nononcology imaging. Here we report a case of advanced pancreatic adenocarcinoma, imaged with both 18 F-FDG and 68 Ga-FAPI-46 PET/CT scans. The result indicated that imaging with 68 Ga-FAPI-46 showed significant improvement in detection of metastases as well as local malignancy recurrence. Moreover, the intensity and SUVs of the lesions were higher in 68 Ga-FAPI-46 scan compared with 18 F-FDG.
Retinoic acid promotes fibrinolysis and may regulate polyp formation
Authors: Masafumi Sakashita, Tetsuji Takabayashi, Yoshimasa Imoto, Tetsuya Homma, Kanako Yoshida, Kazuhiro Ogi, Yukihiro Kimura, Atsushi Kato, Whitney W. Stevens, Stephanie S. Smith, Kevin C. Welch, James E. Norton, Lydia A. Suh, Roderick G. Carter, Kathryn E. Hulse, Sudarshan Seshadri, Jin-Young Min, Kathryn L. Pothoven, David B. Conley, Bruce K. Tan, Kathleen E. Harris, Robert C. Kern, Shinichi Haruna, Yoshinori Matsuwaki, Ryosuke Ochiai, Shigeharu Fujieda, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2022)
Phase 1, dose-escalation study of guadecitabine (SGI-110) in combination with pembrolizumab in patients with solid tumors
Authors: Dionysis Papadatos-Pastos, Wei Yuan, Abhijit Pal, Mateus Crespo, Ana Ferreira, Bora Gurel, Toby Prout, Malaka Ameratunga, Maxime Chénard-Poirier, Andra Curcean, Claudia Bertan, Chloe Baker, Susana Miranda, Nahal Masrour, Wentin Chen, Rita Pereira, Ines Figueiredo, Ricardo Morilla, Ben Jenkins, Anna Zachariou, Ruth Riisnaes, Mona Parmar, Alison Turner, Suzanne Carreira, Christina Yap, Robert Brown, Nina Tunariu, Udai Banerji, Juanita Lopez, Johann de Bono, Anna Minchom
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Data suggest that immunomodulation induced by DNA hypomethylating agents can sensitize tumors to immune checkpoint inhibitors. We conducted a phase 1 dose-escalation trial ( NCT02998567 ) of guadecitabine and pembrolizumab in patients with advanced solid tumors. We hypothesized that guadecitabine will overcome pembrolizumab resistance. Methods Patients received guadecitabine (45 mg/m 2 or 30 mg/m 2 , administered subcutaneously on days 1–4), with pembrolizumab (200 mg administered intravenously starting from cycle 2 onwards) every 3 weeks. Primary endpoints were safety, tolerability and maximum tolerated dose; secondary and exploratory endpoints included objective response rate (ORR), changes in methylome, transcriptome, immune contextures in pre-treatment and on-treatment tumor biopsies. Results Between January 2017 and January 2020, 34 patients were enrolled. The recommended phase II dose was guadecitabine 30 mg/m 2 , days 1–4, and pembrolizumab 200 mg on day 1 every 3 weeks. Two dose-limiting toxicities (neutropenia, febrile neutropenia) were reported at guadecitabine 45 mg/m 2 with none reported at guadecitabine 30 mg/m 2 . The most common treatment-related adverse events (TRAEs) were neutropenia (58.8%), fatigue (17.6%), febrile neutropenia (11.8%) and nausea (11.8%). Common, grade 3+ TRAEs were neutropaenia (38.2%) and febrile neutropaenia (11.8%). There were no treatment-related deaths. Overall, 30 patients were evaluable for antitumor activity; ORR was 7% with 37% achieving disease control (progression-free survival) for ≥24 weeks. Of 12 evaluable patients with non-small cell lung cancer, 10 had been previously treated with immune checkpoint inhibitors with 5 (42%) having disease control ≥24 weeks (clinical benefit). Reduction in LINE - 1 DNA methylation following treatment in blood (peripheral blood mononuclear cells) and tissue samples was demonstrated and methylation at transcriptional start site and 5’ untranslated region gene regions showed enriched negative correlation with gene expression. Increases in intra-tumoural effector T-cells were seen in some responding patients. Patients having clinical benefit had high baseline inflammatory signature on RNAseq analyses. Conclusions Guadecitabine in combination with pembrolizumab is tolerable with biological and anticancer activity. Reversal of previous resistance to immune checkpoint inhibitors is demonstrated.
Caloric Restriction and Weight Loss Are Primary Factors in the Early Tissue-Specific Metabolic Changes After Bariatric Surgery
Authors: Charles Robb Flynn, Robyn A. Tamboli, Joseph Antoun, Reem M. Sidani, Brandon Williams, Matthew D. Spann, Wayne J. English, E. Brian Welch, Sinju Sundaresan, Naji N. Abumrad
Journal: Diabetes Care (2022)

OBJECTIVE To evaluate changes in insulin sensitivity, hormone secretion, and hepatic steatosis immediately after caloric restriction, vertical sleeve gastrectomy (VSG), and Roux-en-Y gastric bypass (RYGB). RESEARCH DESIGN AND METHODS Obese subjects were assessed for 1) insulin sensitivity with hyperinsulinemic-euglycemic clamp with glucose tracer infusion, 2) adipokine concentrations with serum and subcutaneous adipose interstitial fluid sampling, and 3) hepatic fat content with MRI before and 7–10 days after VSG, RYGB, or supervised caloric restriction. RESULTS Each group exhibited an ∼5% total body weight loss, accompanied by similar improvements in hepatic glucose production and hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Leptin concentrations in plasma and adipose interstitial fluid were equally decreased, and reductions in hepatic fat were similar. CONCLUSIONS The improvements in insulin sensitivity and adipokine secretion observed early after bariatric surgery are replicated by equivalent caloric restriction and weight loss.
Longitudinal trajectories of fatigue in early RA: the role of inflammation, perceived disease impact and early treatment response
Authors: Michaël Doumen, Sofia Pazmino, Delphine Bertrand, Diederik De Cock, Johan Joly, René Westhovens, Patrick Verschueren
Journal: Annals of the Rheumatic Diseases (2022)

Objective Fatigue is common in rheumatoid arthritis (RA). We aimed to explore its longitudinal course, predictors and association with disease activity in early RA. Methods Data came from the 2-year treat-to-target trial CareRA (Care in early RA) and its 3-year extension. Fatigue was measured on Visual Analogue Scale, Multidimensional Fatigue Inventory and Short Form-36 (SF-36) vitality. Longitudinal fatigue trajectories were identified with multivariate growth mixture modelling. Early predictors of fatigue and the association of fatigue and its trajectories with disease activity and clinical/psychosocial outcomes were studied with linear mixed models and multilevel mediation. Results We included 356 and 244 patients in the 2-year and 5-year analyses, respectively. Four fatigue trajectories were identified: rapid, gradual, transient improvement and early deterioration, including 10%, 14%, 56% and 20% of patients. Worse pain, mental health and emotional functioning were seen in the early deterioration group. Higher pain, patient global assessment (PGA) and disability (Health Assessment Questionnaire), lower SF-36 mental components, and fewer swollen joints at baseline predicted higher fatigue over 5 years, while early disease remission strongly improved 5-year fatigue. The association between Simple Disease Activity Index and fatigue was mediated by PGA, pain, mental health and sleep quality. Conclusions Although fatigue evolves dynamically over time in early RA, most patients do not achieve sustained fatigue improvement despite intensive disease-modifying antirheumatic drug therapy. Higher 5-year fatigue levels were seen in patients with more perceived disease impact and fewer swollen joints at baseline. Conversely, early inflammatory disease control strongly improved long-term fatigue, pointing towards an early window of opportunity to prevent persistent fatigue.
Ancestrally Reconstructed von Willebrand Factor Reveals Evidence for Trench Warfare Coevolution between Opossums and Pit Vipers
Authors: Danielle H Drabeck, Alexandra Rucavado, Erika Hingst-Zaher, Antony Dean, Sharon A Jansa
Journal: Molecular Biology and Evolution (2022)

Opossums in the tribe Didelphini are resistant to pit viper venoms and are hypothesized to be coevolving with venomous snakes. Specifically, a protein involved in blood clotting (von Willebrand factor [vWF] which is targeted by snake venom C-type lectins [CTLs]) has been found to undergo rapid adaptive evolution in Didelphini. Several unique amino acid changes in vWF could explain their resistance; however, experimental evidence that these changes disrupt binding to venom CTLs was lacking. Furthermore, without explicit testing of ancestral phenotypes to reveal the mode of evolution, the assertion that this system represents an example of coevolution rather than noncoevolutionary adaptation remains unsupported. Using expressed vWF proteins and purified venom CTLs, we quantified binding affinity for vWF proteins from all resistant taxa, their venom-sensitive relatives, and their ancestors. We show that CTL-resistant vWF is present in opossums outside clade Didelphini and likely across a wider swath of opossums (family Didelphidae) than previously thought. Ancestral reconstruction and in vitro testing of vWF phenotypes in a clade of rapidly evolving opossums reveal a pattern consistent with trench warfare coevolution between opossums and their venomous snake prey.